While prior work has suggested that serotonin is involved in modulating tolerance to aversive events, far too little is known about the relationship between serotonin and cognition. Advancing our understanding of the neural and genetic mechanisms through which serotonin influences individual differences in learning to respond to aversive events is a necessary first step towards a deeper understanding of vulnerabilities to mental health disorders such as depression, anxiety, and stress disorders. Toward that end, the primary aim of this project is to study naturally occurring variations in two serotonin genes, how they differentially affect peoples'biases for learning to obtain reward versus learning to avoid punishment, and how these genetic variations in cognitive styles interact with personality and gender. Because many genes that are implicated in mental disorders also show naturally occurring variations in healthy individuals, understanding the function of these genes is a key component of understanding both individual differences in learning and memory, and how genetic variation can contribute to risk for mental disorders. The proposal represents a new cross-disciplinary collaboration between two established cognitive neuroscientists (the PI, Mark Gluck and the Co-I, Catherine Myers) and two geneticists, Emilia Vitale and Annette Lee, consultants to this grant. The primary cognitive measure used will be a novel probabilistic categorization task developed by the PI, Co-PI and colleagues in which subjects are trained to classify four stimuli into two categories. Because two of the stimuli are trained via positive-rewarding feedback to correct answers and two of the stimuli are trained via negative-punishing feedback to incorrect answers, the task allows for analysis of individual differences in sensitivity to positive versus negative feedback during learning. This task, along with personality assessment tools that measure novelty seeking and harm avoidance, provide a means to test the hypothesis that individuals with a genetic predisposition for reduced levels of serotonin in the brain will be biased to process negative feedback at the expense of positive feedback during such learning tasks. The particular genotypes to be evaluated are: (1) a single nucleotide polymorphism, His452Tyr, in the serotonin 2a receptor gene (5-HT2AR) and (2) a 44-nucleotide insertion/deletion in the promoter region of the serotonin transporter gene (5HTTLPR). Individuals with one or both of these less common polymorphisms are predicted to show the highest levels of sensitivity to punishment in learning and highest levels of harm avoidance personality. PUBLIC HEALTH RELEVANCE: Building on prior work suggesting that serotonin is involved in modulating tolerance to aversive events, this research will expand our understanding of the neural and genetic bases of individual differences in learning to predict and respond to aversive events. This, in turn, may lead to a deeper understanding of individual differences in vulnerability to mental health disorders such as depression, anxiety, stress disorders, and eating disorders. Better understanding of the function of serotonin function in healthy individuals may also provide insights into why drug efficacy for some of these disorders may vary across individuals.